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Journal of Adolescent Health 51 (2012) S23–S28
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Review article
Can Traumatic Stress Alter the Brain? Understanding the Implications of Early
Trauma on Brain Development and Learning
Victor G. Carrion, M.D.*, and Shane S. Wong
Stanford Early Life Stress Research Program, Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford,
California
Article history: Received November 22, 2011; Accepted April 18, 2012
Keywords: PTSS; MRI; Hippocampus; PFC; Cortisol; Learning
A B S T R A C T
Background: Youth who experience traumatic stress and develop post-traumatic symptoms secrete higher
levels of the glucocorticoid cortisol than youth with no trauma history. Animal research suggests that excess
corticosterone secretion can lead to neurotoxicity in areas of the brain rich in glucocorticoid receptors such as
the hippocampus and the prefrontal cortex (PFC). These two areas of the brain are involved in memory
processing and executive function, both critical functions of learning.
Methods: In this article, we summarize findings presented at the National Summit for Stress and the Brain
conducted at Johns Hopkins University’s Department of Public Health in April 2011. The presentation
highlighted structural and functional imaging findings in the hippocampus and PFC of youth with posttraumatic stress symptoms (PTSS).
Results: Youth with PTSS have higher levels of cortisol. Prebedtime cortisol levels predict decreases in
hippocampal volume longitudinally. Cortisol levels are negatively correlated with volume in the PFC. Functional imaging studies demonstrate reduced hippocampal and PFC activities on tasks of memory and
executive function in youth with PTSS when compared with control subjects.
Conclusions: Effective interventions for youth with PTSS should target improved function of frontolimbic
networks. Treatment outcome research using these potential markers can help develop more focused
interventions that target the impaired learning of vulnerable youth experiencing traumatic stress.
Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.
Our inner cities are plagued by an epidemic of interpersonal
violence and trauma that affects our nation’s children on a daily
basis. If traumatic stress damages the developing brain and impairs the ability for children to learn, this could have important
public health and education implications. Studies have shown
that children exposed to traumatic stress are more likely to have
poorer school performance [1,2], lower reading achievement [3],
decreased verbal IQ [4], and more days of school absence [5].
Furthermore, childhood trauma has an impact over the entire
lifespan. Although youth exposed to adverse childhood experi-
* Address correspondence to: Victor G. Carrion, M.D., Stanford Early Life Stress
Research Program, Division of Child and Adolescent Psychiatry, Department of
Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Stanford, CA 94305.
E-mail address: [email protected] (V.G. Carrion).
ences are at greater risk for learning and behavior disorders,
adults with a history of adverse childhood experiences have a
higher risk for various health issues, including depression, substance use, and suicidality [6,7].
Trauma acts as a threat to an individual’s well-being, thereby
activating a neurobiological stress response. Although necessary
for survival, chronic and frequent physiological stress responses
can alter brain development, leading to dysregulation of neural
circuitry. Children exposed to traumatic stress may develop posttraumatic stress disorder (PTSD) or its symptoms (PTSS). PTSD is
characterized by three clusters of symptoms: re-experiencing
symptoms, such as flashback memories; avoidance and emotional numbing symptoms, such as inability to recall the trauma; and hyperarousal symptoms, such as difficulties with
concentration. Neuroimaging studies of PTSD in adults have
demonstrated the involvement of two key structures in the
1054-139X/$ - see front matter Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.
http://dx.doi.org/10.1016/j.jadohealth.2012.04.010
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V.G. Carrion and S.S. Wong / Journal of Adolescent Health 51 (2012) S23–S28
pathophysiology of this syndrome: the prefrontal cortex (PFC)
and the hippocampus [8].
The Hippocampus
The hippocampus is a medial temporal brain structure in the
limbic system that plays an essential role in new learning and
memory formation [9]. In healthy individuals, the hippocampus
is engaged during encoding and retrieval of information [10].
However, during and after exposure to a traumatic experience,
physiological hyperarousal may make memories difficult to regulate. The memories may be processed abnormally, leading to
both overrepresentation, such as intrusive thoughts and nightmares, or suppression, inability to recall memories, or selective
amnesia. These cognitive manifestations suggest involvement of
the hippocampus in the pathophysiology of PTSS, specifically as
they relate to learning from previous experience.
Animal research has shown that one potential mechanism of
damage to the hippocampus is through corticosterone, the animal analog to cortisol in humans, which can be neurotoxic if
secreted in high levels [11]. In studies involving rodents, the
number of damaged cells in the hippocampus because of corticosterone exposure was associated with the magnitude of deficits in learning [12].
In human studies of patients with Cushing’s disease, characterized by excessive release of cortisol over long periods, hippocampal volume reductions on neuroimaging have been demonstrated and correlated to deficits in verbal declarative memory
[13]. Similarly, in patients with epilepsy who underwent surgical
resection of the hippocampus, the reduction in left hippocampal
volume correlated with deficits in verbal and visual memory
performance [14].
The Prefrontal Cortex
The PFC is an anterior frontal lobe structure that plays an
essential role in shifting attention and forming stimuli–response
associations, both of which are fundamental cognitive processes
that contribute to learning. In healthy individuals, the PFC supports cognitive control—the ability to filter and suppress information and actions in favor of shifting attention to relevant
information and responses [15]. The PFC is also important for
making the association between stimuli and its rewards, thus
contributing to the formation of response-reinforcement associations and guiding goal-directed actions [16].
However, individuals with PTSS may experience difficulties in
sustaining attention and can be easily distracted. They may also
have difficulties suppressing intrusive memories of the trauma
(e.g., flashbacks, nightmares) and extinguishing fear responses.
These behavioral manifestations of PTSS overlap with the function of PFC, implicating the involvement of PFC in the pathophysiology of PTSS and associated learning impairments.
In support of this hypothesis, animal studies have shown that
rats with PFC lesions were unable to extinguish fear responses
after fear conditioning, whereas this fear response was easily
extinguished when there was no damage to the PFC [17]. Consistent with these animal studies, human imaging studies have
shown that PFC is preferentially active during extinction of fear
[18]. Similarly, human studies have shown that individuals with
lesions to the PFC have deficits in shifting attention and reversal
of stimulus–reward associations, cognitive tasks fundamental to
academic learning [19,20].
Methods
Magnetic resonance imaging (MRI) studies offer a method of
interest to developmental neuroscientists because of their benefits of no radiation exposure and no requirement for contrast. In
this article, we present a review of studies presented at the
National Summit for Stress and the Brain at Johns Hopkins University’s Department of Public Health in April 2011. Results from
studies involving youth with PTSS from our research group that
highlight frontolimbic network deficits were presented. A total
independent sample of 40 youth with PTSS and 38 age- and
gender-matched healthy children was studied across the neuroimaging studies, with 30 of the youth with PTSS and 15 of the
healthy children participating in the study on cortisol. Relevant
research from other investigators is also highlighted to provide
context for interpreting our findings, particularly as to how such
deficits may underlie symptomatology and learning difficulties.
The Discussion section presents the implications of such findings
on the directions for future neuroimaging research in pediatric
PTSD.
Results
Table 1presents a summary of hippocampal and PFC structural and functional imaging findings in youth with PTSS.
The hippocampus
We conducted a longitudinal study to investigate the changes
in hippocampus volume and its relationship to cortisol in children who had been exposed to trauma [21]. In a group of 15
children aged between 8 and 14 years who presented with PTSS
and a history of trauma exposure, we evaluated their initial PTSS
severity and cortisol levels and the changes in their hippocampal
volume over a 12- to 18-month interval. We found that greater
PTSS severity and prebedtime cortisol levels at baseline predicted greater reduction in hippocampal volume, while controlling for pubertal maturation and gender. This was the first longitudinal study on PTSD to document an association between
hippocampal changes with PTSS and with a biological marker of
stress.
A later study by our group further investigated differences in
the hippocampus functioning during a memory task in traumatized children [22]. We studied a group of 16 youth aged between
10 and 17 years with PTSS and a history of interpersonal trauma
in comparison with a group of 11 age- and gender-matched
healthy youth, on a Verbal Declarative Memory Task. The memory task requires encoding 40 unique visually presented nouns
and retrieving 32 of them 5–10 minutes later. Controlling for IQ,
we found that children with PTSS showed reduced activation of
the right hippocampus during memory retrieval compared with
healthy children, as well as decreased retrieval accuracy on the
verbal declarative memory task. Within the PTSS group, the
severity of avoidance and emotional numbing symptoms correlated with reduced left hippocampal activation during retrieval.
These results suggest that difficulties in memory processing by
youth with PTSS may be related to activation deficits of the right
hippocampus. Furthermore, our findings implicate the functional disturbance of the hippocampus in the manifestation of
avoidance and numbing symptoms, which may include the inability to recall important aspects of the trauma and a restricted
range of affect.
Table 1
Summary of hippocampal and PFC imaging findings in children with PTSS from the Stanford Early Life Stress Research Program
Study
Title
PTSS group
Control group
Study design
Findings
Hippocampus
Structural
Carrion et al [21]
Fifteen children aged
between 8 and 14
years with PTSS and
a history of trauma
exposure
None
Carrion et al [22]
Sixteen children aged
between 10 and 17
years with PTSS and
history of
interpersonal
trauma
Eleven age-matched
healthy children
with similar
gender
distribution
Longitudinal study involving
clinical evaluation for PTSD,
salivary cortisol levels, and
structural MRI; analysis of brain
volume changes controlled for
pubertal maturation and gender
An fMRI study comparing the PTSS
group with healthy control subjects
on brain activation during the
Verbal Declarative Memory Task
(encoding and retrieving of visually
presented nouns) with correlation
to PTSD symptoms; analysis
controlled for IQ
Greater PTSS severity and prebedtime cortisol
levels at baseline predicted greater
reduction in hippocampal volume over an
ensuing 12- to 18-month interval
Functional
Stress predicts brain
changes in children:
A pilot longitudinal
study on youth
stress, PTSD, and
the hippocampus
Reduced hippocampal
activity in youth
with PTSS: An fMRI
study
Carrion et al [23]
Attenuation of frontal
asymmetry in
pediatric PTSS
Twenty four children
aged between 7 and
14 years with PTSS
and a history of
trauma exposure
Twenty four ageand gendermatched healthy
children
Children with PTSS showed attenuation of
frontal lobe asymmetry and smaller total
brain and cerebral volumes compared with
healthy control subjects
Richert et al [24]
Regional differences of
the PFC in pediatric
PTSD: An MRI study
Twenty three children
aged between 7 and
14 years with PTSS
and a history of
interpersonal
trauma
Twenty four ageand gendermatched healthy
children
Carrion et al [25]
Decreased prefrontal
cortical volume
associated with
increased bedtime
cortisol levels in
traumatized youth
Thirty children aged
between 10 and 16
years with PTSS and
a history of
interpersonal
trauma
Fifteen age- and
gender-matched
healthy children
MRI study comparing PTSS group
with healthy control subjects,
with focused analysis of
amygdala and hippocampus
volumes, controlling for total
brain volume
MRI study comparing regional PFC
volumes of PTSS group with
healthy control subjects, with
correlation to PTSD
symptomatology and functional
impairment. Analysis controlled
for total cranial gray matter
volume,and comorbid major
depressive disorder and ADHD
MRI study comparing PTSS group
with healthy control subjects on
total brain tissue volume and
regional PFC volumes areas,
with correlation to diurnal
cortisol secretion. Analysis
controlled for age and IQ
Carrion et al [26]
PTSS and brain
function during a
response-inhibition
task: An fMRI study
in youth
Sixteen medicationnaive children with
PTSS between 10
and 16 years
Fourteen age- and
gender -matched
healthy children
Prefrontal cortex
Structural
Functional
fMRI study comparing PTSS group
with healthy control subjects on
the go/no-go (responseinhibition) task, while
controlling for IQ
Children with PTSS showed a larger volume of
gray matter in the delineated middleinferior and ventral regions of the PFC
compared with healthy control subjects.
Within the PTSS group,greater functional
impairment scores were associated with
reduced dorsal PFC gray matter volume
Children with PTSS showed reduced total
brain tissue, reduced total cerebral gray
volume, and decreased left ventral and left
inferior prefrontal gray volumes compared
with healthy children. Within the PTSS
group, the high prebedtime cortisol levels
were associated with reduced left ventral
PFC gray volume
Children with PTSS showed reduced middle
frontal cortex and increased left medial
frontal gyrus and anterior cingulate gyrus
activation compared with healthy control
subjects during response-inhibition. Within
the PTSS group,children with self-injurious
behaviors had increased insula and
orbitofrontal activation compared with
children without self-injurious behaviors,
with greater insula activation correlated to
greater PTSS severity
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PFC ⫽ prefrontal cortex; PTSS ⫽ post-traumatic stress symptoms; PTSD ⫽ post-traumatic stress disorder; fMRI ⫽ functional magnetic resonance.
Children with PTSS showed reduced activation of
the right hippocampus during memory retrieval
compared with healthy children. Within the
PTSS group, the severity of avoidance and
emotional-numbing symptoms correlated with
reduced left hippocampal activation during
retrieval
V.G. Carrion and S.S. Wong / Journal of Adolescent Health 51 (2012) S23–S28
Imaging type
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V.G. Carrion and S.S. Wong / Journal of Adolescent Health 51 (2012) S23–S28
In adults with PTSS, including those with a childhood history
of abuse, studies have similarly demonstrated volume reductions and hypoactivation in the hippocampus associated with
deficits in memory performance [8,27,28]. However, pediatric
studies limited to structural neuroimaging and cross-sectional
design have not replicated findings of smaller hippocampus
among children [29]. The discrepancy between the longitudinal
finding of reduced hippocampus in our recent study and unremarkable cross-sectional studies implicates neurodevelopmental processes that are not observed in the hippocampus early in
the course of PTSS. For example, a study of rats exposed to early
stress and killed at different ages showed that differences in the
hippocampus only emerge after young adulthood [30]. Cortisol
likely plays a key role because elevated salivary cortisol levels
have been found in maltreated children with PTSD [31], and
cortisol can be neurotoxic if secreted in high levels [11]. Indeed,
cortisol level differences in individuals with PTSS persist through
adulthood with abnormal declines in the context of hypothalamic–
pituitary–adrenal axis alterations [32]. Thus, reductions in hippocampus volume secondary to cortisol neurotoxicity may be
found only after years of chronic PTSS. In the larger context of
hippocampus research in PTSS, our findings suggest that youth
with PTSS have deficits in hippocampus structure and functioning, which are associated with impairments in memory processing that may underlie learning difficulties and PTSS associated
with maladaptive processing of traumatic memories.
The prefrontal cortex
In an early study, we investigated the hypothesis of brain
volume differences in children with PTSS [23]. In a group of 24
children between the ages of 7 and 14 years with PTSS and a
history of trauma exposure, compared with 24-age- and gendermatched healthy youth, we found that children with PTSS
showed attenuation of frontal lobe asymmetry and smaller total
brain and cerebral volumes compared with healthy control subjects. Specifically, children in the control group showed significant right more than left differences across the hemispheres,
whereas no significant asymmetry in frontal hemisphere volumes was detected for the PTSS subjects.
In a later study assessing 23 children with PTSS and a history
of interpersonal trauma, we found that children with PTSS
showed a larger volume of gray matter in the delineated middle
inferior and ventral regions of the PFC compared with healthy
control subjects [24]. Within the PTSS group, greater functional
impairment scores were associated with reduced dorsal PFC gray
matter volume. This suggests that the neuroanatomy of the dorsal PFC may influence some of the symptoms experienced by
children with PTSS.
Having identified frontal structural differences, we sought to
understand the functional significance of such findings. In a functional study (functional MRI [fMRI]) of brain activation during a
response-inhibition task, we studied 16 children with PTSS in
comparison with 14 healthy children [26]. We found that children with PTSS showed reduced middle frontal cortex and increased left medial frontal gyrus and anterior cingulate gyrus
activation compared with healthy control subjects during a
response-inhibition task. Notably, this region overlaps with the
ventromedial PFC, which plays a role in the extinction of a conditioned fear response [33]. This suggests that diminished middle frontal activity and enhanced medial frontal activity during
response-inhibition tasks may represent both a neurofunctional
marker and a pathophysiological mechanism of development for
PTSS. Furthermore, we also found that within the group of children with PTSS, children with self-injurious behaviors had increased insula and orbitofrontal activation compared with children without self-injurious behaviors, with greater insula
activation correlated to greater PTSS severity [26]. By implicating
a self-injurious subtype of PTSD that may represent a failure of
response inhibition associated with more severe PTSS and
greater insula activation, this finding suggests that neuroimaging
may further our understanding of the heterogeneity in PTSD by
identifying clinically relevant biological subtypes.
In a follow-up study, we investigated the relationship of cortisol to PFC function among 30 children with PTSS and a history of
interpersonal trauma, in comparison with 15 age- and gendermatched healthy control subjects [25]. We found that children
with PTSS showed reduced total brain tissue, reduced total cerebral
gray volume, and decreased left ventral and left inferior prefrontal
gray volumes compared with healthy children. Furthermore, in the
full sample including both PTSS and healthy children, high prebedtime cortisol levels were associated with reduced left ventral PFC
gray volume. These findings suggest another link between cortisol
secretion after traumatic stress and its neurotoxic effect on brain
development, this time in the PFC.
Structural neuroimaging of the PFC among youth with PTSS
has repeatedly demonstrated abnormalities, but the direction of
regional volume change is inconsistent across studies. As with
the association of cortisol with PTSS, time since trauma may
moderate the direction of developmental differences. In addition
to time-related factors, the inconsistent findings across studies
may be related to variations across studies in methodology for
volumetric imaging and analysis, in sample demographics of age,
developmental stage, and gender, or in clinical history of abuse
subtype and PTSS severity. Specifically, in comparing a more
recent structural imaging study with an early study, we acquired
imaging with a 3.0-T MRI compared with 1.5-T MRI, analyzed
volumes using eight PFC subdivisions compared with two, had a
demographic sample with a higher ratio of females, greater average age, and Tanner stage, and had a clinical sample with a
higher ratio of subthreshold PTSD and physical abuse compared
with other trauma subtypes [24,25].
Neuroimaging studies of children with PTSS by other investigators have replicated our findings of abnormalities in PFC structure among children with PTSS. For example, De Bellis et al [34]
found reduced white matter volume in the PFC among children
with a history of maltreatment. Furthermore, brain abnormalities in the PFC have been consistently demonstrated in studies of
adults with PTSS, including reduced volume and hypoactivation
during tasks of attention, memory, and emotional cognition
[8,35]. Taken together, these findings suggest that youth with
PTSS have deficits in key areas of the PFC responsible for cognitive control attention, memory, response inhibition, and emotional reasoning— cognitive tools that may be necessary for
learning and therapeutic processing of trauma.
Discussion
We presented data supporting anatomical and neurofunctional differences between youth with PTSS secondary to interpersonal trauma and healthy youth. One important question is
whether brain abnormalities found in youth with PTSD represent
pre-existing risk factors for PTSS, or the consequences of traumatic stress. We found that more severe PTSS and higher cortisol
V.G. Carrion and S.S. Wong / Journal of Adolescent Health 51 (2012) S23–S28
levels in maltreated children predicted greater hippocampal volume reduction over time [21]. In contrast, Gilbertson et al [36]
found that twins of veterans with PTSS, but not exposed to
combat trauma, had a reduced hippocampal volume. These studies suggest that a decreased hippocampal volume may be both a
risk factor and a consequence of PTSS. This highlights the importance of longitudinal studies that can investigate developmental
changes. Furthermore, although research may inform clinical
practice more directly in the future, the uncertain significance of
neuroimaging markers dictates that current interventions for
pediatric trauma should remain targeted toward youth with
clinical symptomatology impairing function, rather than youth
with particular biological markers.
However, neuroimaging research investigating biological markers may inform clinical practice by promoting development of evidence-based interventions. More specifically, individual interventions can gain empirical evidence by demonstrating an effect on
putative biological markers—markers that may represent not only
reversible functional impairments but also subtypes of PTSD or
predictors of specific treatment response. Notably, using an animal model of PTSD, Hendriksen et al [37] demonstrated that
recovery from trauma-induced impairments is associated with
cell growth in the hippocampus and alterations in neurotransmitter activity in the PFC and hippocampus. Furthermore, recent
studies incorporating neuroimaging in adult PTSD treatment research showed that psychotherapy can modify brain activity in
the PFC and associated neural circuits responsible for cognitive
control of attention, memory retrieval, and emotional reasoning
[38 – 40]. This small, but growing, body of research suggests that
the impact of neuroimaging on treatment– outcome research is
promising, by potentially strengthening empirical evidence of
treatment efficacy.
In this review, we have identified biological markers of pediatric PTSS including structural and functional abnormalities in
the PFC and hippocampus, further associated with abnormal
cortisol levels. Such findings suggest that interventions that effectively reduce cortisol levels early in development and improve frontal and limbic function may be particularly effective at
facilitating recovery from PTSS and enhance resilience to learning impairments. For example, identifying gaps in a child’s
trauma narrative as he or she integrates the experience into
history may improve hippocampus function and memory,
whereas behavioral interventions that develop cognitive control
of attention may enhance prefrontal activity and executive functioning.
Limitations of the current research include a predominance of
correlational studies that cannot disentangle causality, and the
small sample sizes, although these are representative of neuroimaging studies. Given the few longitudinal and functional imaging studies of youth with PTSS, there is a need for replication of
our findings in future research. Further research will need to
elucidate whether interventions that improve frontal and limbic
activity will translate to improvements in the learning difficulties and symptoms of pediatric PTSD.
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